I. Field of the Invention
The present invention relates generally to the fields of molecular biology and oncology. More particularly, it concerns methods and compositions involving microRNA (miRNAs) molecules and cancer diagnosis and/or prognosis. Certain aspects include applications for miRNAs in diagnosis and prognosis of thyroid cancer.
II. Background
The vast majority of thyroid cancers occur randomly. However, several reports have shown that the incidence of thyroid cancer is higher in individuals exposed to radiation, whether the radiation is from treatment for disease (e.g., for Hodgkin's and Graves' diseases) or from accidental exposure. Childhood radiation exposure is the only well-documented risk factor for the development of thyroid cancer. Also, medullary thyroid cancers, a rare form of thyroid cancer, have been linked to a genetic predisposition, and approximately 5% of non-medullary thyroid cancers are hereditary. Patients with a history of Graves' disease, thyroiditis, goiter, or a family history of familial adenomatous polyposis (FAP) have an elevated risk of developing thyroid cancer. Most thyroid cancers are indolent and usually treatable when detected early. A subset of thyroid tumors can however behave aggressively.
Thyroid tumors encompass a variety of lesions that range from benign adenoma to malignant tumors. The cancers can be well-differentiated, poorly-differentiated, or undifferentiated (anaplastic). More than 95% of thyroid cancers are derived from thyroid follicular cells, 2-3% of cancers (medullary thyroid carcinomas) are derived from the thyroid C cells, and approximately 1% of tumors are anaplastic. Approximately 80% of all thyroid cancers are follicular-cell derived papillary thyroid carcinomas (PTC), which may spread to local lymph nodes. The tall cell variant (TCV) of PTC represents the most common aggressive form of PTC. The second most common tumor type, approximately 15% of all cancers, is follicular thyroid carcinoma (FTC), which may be of conventional or oncocytic (Hurthle) cell type. FTC can develop either de novo or from a pre-existing benign follicular adenoma and is characterized by haematogenous spread. Both PTC and FTC are well-differentiated cancers that are usually indolent and have a good prognosis. In contrast, poorly-differentiated carcinomas (PDC) and anaplastic thyroid cancers (ATC) are highly aggressive and lethal tumors that can develop de novo or from the progression of pre-existing PTC or FTC. Fortunately, ATC are rare, accounting for ˜5% of all thyroid cancers, and easily diagnosed
Although thyroid cancer is relatively rare, thyroid nodules are very common. Because the great majority of thyroid nodules are benign, a continuing challenge for physicians is to accurately distinguish benign nodules from malignant nodules. Cytology of fine needle aspiration biopsies, the current standard for evaluating malignancy of thyroid nodules, frequently lacks specificity and is incapable of determining malignancy in up to 40% of cases. Recently, molecular testing for mutations or translocations in genes such as BRAF, RAS, RET/PTC, and PAX8/PPARγ has been applied to thyroid cancer diagnosis. However, some thyroid cancers do not carry mutations in these genes and some of these markers have low specificity for malignancy.
Recently, microRNAs have been implicated in various cancers, including thyroid cancer. microRNAs (miRNAs) are short RNA molecules (16-29 nucleotides in length) that arise from longer precursors, which are transcribed from non-protein coding genes (Carrington et al., 2003). The precursors are processed by cellular proteins to generate short double-stranded miRNA. One of the miRNA strands is incorporated into a complex of proteins and miRNA called the RNA-induced silencing complex (RISC). The miRNA guides the RISC complex to a target mRNA, which is then cleaved or translationally silenced, depending on the degree of sequence complementarity of the miRNA or its target mRNA (Bagga et al., 2005; Lim et al., 2005).
A need exists for additional thyroid cancer markers that are capable of distinguishing benign from malignant thyroid nodules and distinguishing among the different types of thyroid cancers.